I. Field of the Invention
The invention relates to optical methods and apparatus for the diagnosis of cervical precancers.
II. Related Art
Cervical cancer is the second most common malignancy among women worldwide. In 1995, it was estimated that 4,800 deaths will occur in the United States alone from this disease and 15,800 new cases of invasive cervical cancer will be diagnosed. Although early detection of cervical precancer has played a central role in reducing the mortality associated with this disease over the last 50 years (G. H, Anderson, British Med J, 296, 975 (1988), which is hereby incorporated by reference, the incidence of pre-invasive squamous carcinoma of the cervix has risen dramatically, especially among women under the age of 35 (T, C. Wright, R. J., A. Ferenczy, "Cervical Intraepithelial Neoplasia" in Blaustein's Pathology of the Female Genital Traci, (Springer-Verlag, New York, 1994), p. 156), which is hereby incorporated by reference. Existing screening and detection techniques, the Pap smear and colposcopy, have several deficiencies that prevent efficient management of an otherwise controllable disease. The primary screening tool is the Pap smear, which has a high false negative error rate of 15-40% due to sampling and reading errors (L. G. Koss, J Am Med Assoc, 261, 737 (1989), which is hereby incorporated by reference. Colposcopy, which usually follows an abnormal Pap smear, requires extensive training and its accuracy is variable and limited even in the hands of expert practitioners (M. F. Mitchell, "Diseases of the Female Lower Genital Tract" in Operative Gynecology, (W. B. Saunders, Philadelphia, 1993), p 231), which is hereby incorporated by reference. The mortality of cervical cancer among women under 50 years increased by 3% between 1986 and 1990, all preventable, and this trend may continue unless further improvements are made in current detection techniques (B. A. Miller, L. A. G. Flies, B. F. Hankey, Kosary, A. Harras, S. S. Devesa, B. K. Edwards, Seer Cancer Statistics Review 1973-1990, (US Department of Health and Human Services, Bethesda, 1993), p. v.1.), which is hereby incorporated by reference.
Recently, fluorescence, infrared absorption and Raman spectroscopes have been proposed for cancer and precancer screening and diagnosis (R. R. Alfano, G. C. Tang, A. Pradhan, W. Lam, D. S. C. Choy, A. Opher, IEEE Journal of Quantum Electronics, QE-23, 1806 (1987).; J. Hung, S. Lam, J. C. LeRiche, B. Palcic, Lasers Surg Med, 11, 99 (1991); R. M. Cothren, R. Richards-Kottum, M. V. Sivak, M. Fitzmaurice, R. P. Rava, G. A. Boyce, G. B. Hayes, M. Doxtader, R. Blackman, T. Ivanc, M. S. Feld, R. E. Petras, Gastrointest Endoscop, 36, 105 (1990); W. S. Glassman, C. H. Liu, G. C. Tang, S. Lubicz, R. R. Alfano, Lasers in Life Sciences, 5, 49 (1992); W. Lohmann, J. Mu.beta.mann, C. Lothmann, W. Kunzel, Euro Jour Obstet Gynecol Reprod Biol, 31, 249 (1989); N. Ramanujam, M. F. Mitchell, A. Mahadevan, S. Thomsen, R. Richards-Kortum, Proc Natl Acad Sc, 91. 10193 (1994);, D. C. B. Redd, Z. C. Feng, K. T. Yue, T. S. Gansler, Appl Spectr, 47, 787 (1993), which are all hereby incorporated by reference. Many groups have successfully demonstrated the potential of spectroscopic techniques to improve diagnosis in various organ systems (M. Motamedi, R. J. Erckens, M. J. Goetz Jr., J. P. Wicksted, G. L. Cote, W. F. March, SPIE, 2388, (1995); Y. Ozaki, A. Mizuno, SPIE, 1403, (1990); C. H. Lui, B. B. Das, W. L. Sha Glassman, G. C. Tang, K. M. Yoo, H. R. Zhu, D. L. Akins, S. S. Lubicz, J. Cleary, R. Prudente, E. Cellmer, A. Caron, R. R. Alfano, J Photochem Photobiol B: Biol, 16, 187 (1992); M. S. Feld, J. F. Brennan III, A. Berger, R. Manoharn, Y. Wang, SPIE, 2388, 99 (1995); R. R. Alfano, C. H. Lui, W. L. Sha, H. R. Zhu, D. L. Akins, J. Cleary, R. Prudente, E. Cellmer, Lasers in Life Sc, 4, 23 (1991); J. F. Brennan III, T. J. Fomer, Y. Wang, A. M. Tercyak, R. S. Lees, R. R. Dasari, J. R. Kramer, M. S. Feld, SPIE, 2388, 105 (1995); J. J. Baraga, M. S. Feld, R. P. Rava, Appl Spectr, 46, 187 (1992)., Y. Wang, R. L. McCreery, Anal Chem, 61, 2647 (1989)., A. Mahadevan, N. Ramanujam, M. F. Mitchell, A. Malpica, S. Thomsen, R. Richards-Kortum, SPIE, 2388, 110 (1995), all of which are hereby incorporated by reference. Intrinsic tissue fluorescence has been used to differentiate normal and abnormal tissues in the human breast and lung, bronchus and gastrointestinal tract. Fluorescence spectroscopy has been shown to be a promising technique for the clinical diagnosis of cervical precancer and extensive clinical trials show that its performance is similar to that of colposcopy in expert hands.
Multivariate statistical techniques have been used to diagnose cervical precancers based on fluorescence spectra acquired at multiple excitation wavelengths. A prospective evaluation of the algorithms indicates that at 337 nm excitation, normal tissues can be differentiated from precancers with a sensitivity of 91% and specificity of 82%. In addition, spectra at 460 nm excitation can differentiate normal cervix and precancers with a sensitivity and specificity of 91% and 75.5%, respectively, as well as differentiate high grade and low grade precancers with a sensitivity and specificity of 80% and 76%, respectively.
To further improve the diagnostic capability of spectroscopy for detection of cervical precancers, Raman spectroscopy has been considered. In comparison with fluorescence, Raman signals are weak and require sensitive instrumentation for detection. However, only a limited number of biological molecules contribute to tissue fluorescence, most with broadband emission. Many more molecules are Raman-active, with fingerprint spectra providing molecular specific information that can be applied to diagnose diseased tissue. As a result, in recent years, several groups have studied the potential of Raman spectroscopy for disease detection. Alfano et al. have used Fourier Transform Raman spectroscopy to detect gynecologic malignancies. Several groups have applied Raman spectroscopy to breast cancer detection. Feld et al. have demonstrated the use of NIR and UV resonance Raman spectroscopy for identification of colon cancer and atherosclerosis.
Nonetheless, automated diagnostic methods with improved diagnostic capabilities are needed to allow faster, more effective patient management and potentially further reduce mortality.